Premenstrual syndrome (PMS) is a widely used name for a condition that occurs in menstruating women. PMS is defined as the occurrence of both physical and emotional symptoms clustered during the second half of the menstrual cycle, which may persist through menstruation with a relatively symptom free period from the end of menstruation to mid-cycle. Approximately 70% of women experience some PMS symptoms, and 20% of this group suffer from some degree of incapacitation.
The symptoms of PMS appear to become more severe with age, particularly after menopause. Premenstrual syndrome is generally considered to be a neuroendocrine dysfunction (hormonal dysfunction.) Psychological symptoms include anxiety, depression, irritability, fatigue, changes in libido, insomnia, angry outbursts, mood swings, and crying for no apparent reason. Neurological symptoms include headaches, dizziness, lack of concentration, altered motor skills, and loss of sense of smell. Other symptoms include acne, herpes, facial pigmentation, breast pain, palpitations, edema, shortness of breath, respiratory problems, abdominal bloating, constipation, food cravings, compulsive eating, and joint and muscle pain. While these symptoms have been identified as the most commonly reported symptoms associated with PMS, other symptoms may occur in individual cases.
Despite the prevalence of PMS, the cause of PMS remains unknown. One current theory proposes that the condition originates in the central nervous system as the result of an imbalance in the production of natural opiates See, e.g., Reid and Yen, Am. J. Obstet Gynecol., v. 139, no. 1, pp. 88-104 (1981). This theory has not been proven in practice. Research has also focused on alterations in the progesterone-estrogen ratio or the level of luteinizing hormone (LH) as the cause of PMS, but no such alterations have been observed. See Backstrom et al., Journal of Steroid Biochemistry, vol. 7, pp. 473-476 (1976) and Coulson, Medical Hypotheses, 19:243-255 (1986). Low sex hormone binding globulin (SHBG) capacity has also been described as linked to PMS. See Dalton, J. Steroid Biochem., Vol. 20, No. 1, pp. 437-439 (1984).
Prior to the present invention, no conclusive biochemical marker was known for PMS. Diagnosis therefore has depended upon empirical analysis of symptoms. The patient is typically asked to keep a daily chart of symptoms such as the foregoing for a period of at least a month, often longer. The physician is then left with the task of discerning whether a PMS pattern of symptoms is present. This can prove difficult because the symptoms of PMS overlap symptoms of many other conditions, and some patients may suffer from both PMS and another condition which manifests PMS-like symptoms. Thus, this method of detecting PMS is tedious, uncertain, and lacks scientific credibility.
No clear connection has previously been made between human luteinizing hormone (LH) and PMS. LH is a glycoprotein hormone having a molecular weight of about 28,000 secreted by the pituitary in response to gonadotropin releasing hormone produced by the hypothalamus. LH is composed of two dissimilar molecular subunits, referred to as the alpha and beta subunits. It has been proposed that the beta subunit gives the hormone its target organ specificity and immunologic properties. See Rapid LH, Serono Diagnostics Protocol, p.1. HCG, human chorionic gonadotropin, has the same beta subunit as LH, and immunization experiments using hCG have been attempted. See Tsong, Chang and Nash, Journal of Reproductive Immunology, 7: 139-149, 151-162, and 163-169 (1985). LH, in combination with follicle stimulating hormone, causes ovarian changes during the female menstrual cycle. An LH surge occurs with ovulation. See generally Johnson et. al., Immunization of Heifers against LH-RH, hCG, and bLH, J. Amer. Sci. (in press).
A variety of conventional immunoassay systems are available for detecting the presence of LH in blood, plasma or urine. For such purposes, human LH has been injected into animals, typically rabbits, which generate rabbit-produced anti-luteinizing hormone (anti-LH) antibodies. Such antibodies are then used as part of a conventional immunoassay system, such as a radioimmunoassay. The extent of the reaction between the anti-LH antibodies and the LH present in the patient sample indicates the level of LH in the sample. Such assays are useful for the diagnosis of conditions associated with elevated or decreased levels of LH. See, for example, Tietz, Clinical Chemistry, pp. 1031-1032 (1986), Gradwohl's Clinical Laboratory Methods and Diagnosis, pp. 448-450, 5th Ed. (1980), Jawetz et. al., Review of Medical Microbiology, pp. 344-345, 12th Ed. and the above-noted Serono Diagnostics Protocol at pages 17-18.
One well known assay for LH is a competitive binding radioimmunoassay as described in the above cited Serono Diagnostics Protocol. According to this procedure, LH in a sample competes with I.sup.125 -labelled LH for a limited number of anti-LH antibodies. The amount of radioactive LH bound to anti-LH antibodies is inversely proportional to the amount of LH present in the sample. A second antibody which binds to the anti-LH antibody together with a polyethylene glycol solution are used to precipitate antibody-bound LH and thereby separate it from free (unreacted) LH. After centrifugation and decanting of the supernatant, the precipitate containing the antibody-bound LH, both labelled and unlabelled, may be analyzed in a standard scintillation counter which in effect detects the amount of I.sup.125 present. This reading is then used to calculate the LH level in the sample by comparison to results obtained for standards containing known amounts of LH. The standard samples are used to create a standard curve (graph) on which the concentration of the test sample may be found by interpolation. The procedure is typically repeated for control samples obtained from a normal subject in order to determine whether the level of LH is depressed, elevated or normal in the patient.
Although anti-LH antibodies have been raised in animals for diagnostic purposes, there has previously been no evidence that such antibodies exist naturally as circulating antibodies in the human body. In general, the immune system of an animal produces antibodies only in response to foreign substances, not to substances which occur naturally in the body. An autoimmune response, i.e. where the body produces an antibody against a substance the body itself produces, is highly unusual. One such autoimmune response has been observed for certain thyroid hormones T.sub.2 and T.sub.3, as described in Harrison, Principles of Internal Medicine, p. 1738 (1987). Harrison further describes detection of such antibodies using labeled hormone.
A variety of methods for treating PMS have been proposed, including diet, exercise, and drug treatments, as described in Lyon et. al., Journal of Reproductive Medicine, Vol. 29, No. 10, pp. 705-711 (1984). One such method involves administering the hormone progesterone to a PMS patient. Progesterone is a naturally occurring steroidal sex hormone also known as pregn-4-ene-3,20-dione. Oral administration of progesterone for PMS treatment has been specifically studied. See, e.g., Maxson et. al., Fertility and Sterility, Vol 44, No. 5, pp. 622-626 (1985), Dennerstein et. al., British Medical Journal, 290:1617 (1985), Dalton, J Steroid Biochem, Vol. 20, No. 1, pp. 437-439 (1984) and Gonzalez, JAMA Medical News, Vol. 245, No. 14, pp. 1394-1396 (1981).
A wide variety of pharmaceutical compositions containing progesterone and a carrier or vehicle are known. For PMS treatment, oral forms of progesterone, such as those decribed in Meli U.S. Pat. No. 3,284,303 issued Nov. 8, 1966, Leeson U.S. Pat. No. 3,862,311 issued Jan. 21, 1975, and Besins U.S. Pat. No. 4,196,188 issued Apr. 1, 1980, have been found particlarly effective. It has been found, in particular, that oral administration of micronized progesterone in safflower oil as a carrier is effective for treating the symptoms of PMS.
The present invention provides a method for the detection of premenstrual syndrome (PMS) which utilizes a reliable biochemical marker for PMS and thus eliminates the guesswork involved in PMS diagnosis. Patients screened according to this method can then be effectively treated for PMS symptoms as described hereafter.